As an independent investigator, I am interested in understanding the molecular mechanisms controlling cellular differentiation. The self-renewing mammalian skin is an excellent model system to study this process. My research team, situated in the Department of Biological Chemistry at the University of California-lrvine, focuses on the mouse ovo family of genes, which are required for the differentiation of the epidermis and hair follicles. The long-term goal of my research program is to use these mouse ovo (movo) genes as a useful molecular handle to study how proliferative cells differentiate into highly specialized terminal cells in the skin that play important roles in protection, sensation, temperature regulation, and social interaction. For the next 5-year period, I propose two specific aims: 1) Characterize the biological functions ofmovo genes. We will characterize the embryonic lethal phenotype of conventional movo2 knockout mice, the generation of which was supported by my R01 grant. We will specifically test the hypothesis that movo2 is a -lownstream target of the Wnt/beta-catenin/LEF signaling pathway during embryonic development. We will characterize the function of movo2 in epidermal and hair follicle differentiation through the generation and analysis of skin-specific movo2 knockout mice. Finally, we will test the putative functional "redundancy/compensation between movo1 and movo2 by generating and analyzing double mutants. 2) characterize the molecular and cellular functions of movo genes. We will investigate the role of movo genes in "egulating gene expression and cellular differentiation. We will specifically test the hypothesis that mOvol 3rotein represses proliferation control genes such as c-Myc and Id2 by competing for binding with the Myb transcriptional activators, thereby shunting the epidermal and hair follicle cells down a terminal differentiation 3athway. We will also characterize the transcription repressor activity of mOvo and study interacting proteins n order to understand the mechanism by which mOvo proteins regulate transcription. Finally, we will examine Nhether mOvo proteins are involved, directly or indirectly, in actin cytoskeleton-driven processes. This research will utilize my existing expertise in biochemistry, molecular biology, and mouse developmental genetics. It will also allow me to acquire new skills in the areas of molecular embryology and bioinformatics. A K02 award will greatly facilitate my continued development as a research scientist, and help me to achieve my goal of using a multi-disciplinary approach to address important biological questions.